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1.
J Immunother Cancer ; 10(8)2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35922089

RESUMO

The advent of immune checkpoint inhibitors has reinvigorated the field of immuno-oncology. These monoclonal antibody-based therapies allow the immune system to recognize and eliminate malignant cells. This has resulted in improved survival of patients across several tumor types. However, not all patients respond to immunotherapy therefore predictive biomarkers are important. There are only a few Food and Drug Administration-approved biomarkers to select patients for immunotherapy. These biomarkers do not consider the heterogeneity of tumor characteristics across lesions within a patient. New molecular imaging tracers allow for whole-body visualization with positron emission tomography (PET) of tumor and immune cell characteristics, and drug distribution, which might guide treatment decision making. Here, we summarize recent developments in molecular imaging of immune checkpoint molecules, such as PD-L1, PD-1, CTLA-4, and LAG-3. We discuss several molecular imaging approaches of immune cell subsets and briefly summarize the role of FDG-PET for evaluating cancer immunotherapy. The main focus is on developments in clinical molecular imaging studies, next to preclinical studies of interest given their potential translation to the clinic.


Assuntos
Imunoterapia , Neoplasias , Anticorpos Monoclonais/uso terapêutico , Humanos , Imunoterapia/métodos , Imagem Molecular , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Tomografia por Emissão de Pósitrons/métodos
2.
J Nucl Med ; 63(8): 19N-20N, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35914823
3.
JACC Cardiovasc Imaging ; 15(8): 1458-1470, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35926905

RESUMO

BACKGROUND: Antibody-based constructs for molecular imaging and therapeutic delivery provide promising opportunities for the diagnosis and treatment of atherosclerosis. OBJECTIVES: The authors aimed to generate and characterize immunoglobulin (Ig)G monoclonal autoantibodies in atherosclerosis for targeting of novel molecular determinants. METHODS: The authors created hybridomas from an unimmunized low-density lipoprotein (LDL) receptor-deficient (Ldlr-/-) mouse and selected an IgG2b isotype autoantibody, LO9, for further characterization. RESULTS: LO9 reacted well with native LDL bound to immobilized matrix components and less well to oxidized LDL. LO9 binding to immobilized native LDL was not neutralized by fluid-phase native LDL, indicating an adhesion-dependent epitope. The authors localized the epitope to a 20 amino-acid peptide sequence (P5) in the globular amino-terminus of apolipoprotein B. LO9 reacted with antigen in mouse atherosclerosis and in both human stable and ruptured coronary atherosclerosis. Furthermore, in vivo near-infrared fluorescence molecular tomographic imaging, and ex vivo confocal microscopy showed that intravenously injected LO9 localized beneath endothelium of the aortic arch in Ldlr-/- mice, in the vicinity of macrophages. CONCLUSIONS: The authors believe LO9 is the first example of an IgG autoantibody that reacts with a native LDL epitope revealed by adherence to tissue matrix. Antibodies against adherent native LDL have potential as molecular targeting agents for imaging of and therapeutic delivery to atherosclerosis.


Assuntos
Aterosclerose , Lipoproteínas LDL , Animais , Anticorpos Monoclonais , Aterosclerose/metabolismo , Autoanticorpos/química , Epitopos , Humanos , Imunoglobulina G , Lipoproteínas LDL/química , Lipoproteínas LDL/metabolismo , Camundongos , Imagem Molecular , Valor Preditivo dos Testes
5.
Rev. esp. med. nucl. imagen mol. (Ed. impr.) ; 41(4): 223-230, jul. - ago. 2022. ilus, graf, tab
Artigo em Espanhol | IBECS | ID: ibc-ADZ-774

RESUMO

Objetivo: Conocer el estado actual de la técnica de localización radioguiada de lesiones no palpables de mama con o sin indicación de biopsia selectiva de ganglio centinela —ROLL, SNOLL y semillas de 125I— mediante la realización de una encuesta nacional elaborada por el Grupo de Trabajo de Cirugía Radioguiada (GTCRG) de la Sociedad Española de Medicina Nuclear e Imagen Molecular (SEMNIM). Material y métodos: En octubre del 2020 se envió la encuesta, en formato digital, a los distintos servicios de Medicina Nuclear de nuestra geografía. Se dio un tiempo de respuesta de 2meses con prórroga de 15 días. Se ha obtenido el número de procedimientos ROLL/SNOLL de cada centro y la metodología utilizada, recogiendo importantes detalles técnicos. Además, se ha incluido un apartado específico sobre las semillas de 125I. Los resultados se volcaron de forma automática en una hoja de cálculo Excel 2007 para su posterior análisis con el mismo programa. Resultados: La encuesta fue contestada por 55 centros; 21 utilizan arpón mientras que los 34 restantes emplean distintas técnicas de cirugía radioguiada (CRG) para la localización de lesiones no palpables de mama, desglosando los resultados en 13apartados. La dosis de trazador habitualmente utilizada es de 111 MBq para la técnica ROLL y de 222 MBq para la técnica SNOLL, con un volumen de 0,2ml. El protocolo más habitual es el de 2días. El 26% de los centros que realiza CRG utiliza semillas de 125I tanto para la detección de lesiones mamarias como de ganglios sospechosos/patológicos, siendo el tiempo entre la implantación y la extirpación es de unos 3 días, con posterior control radiológico en la mayoría de los casos. Conclusión: La encuesta pone de manifiesto la relevancia de la cirugía radioguiada en el manejo de los pacientes con cáncer de mama en las diferentes etapas de la enfermedad, con disparidad en la implementación de las nuevas técnicas y herramientas (AU)


Objective: To know the current status of the technique of radioguided localisation of non-palpable breast lesions with or without indication for selective sentinel node biopsy -ROLL, SNOLL and 125I seeds- by conducting a national survey developed by the Working Group on Radioguided Surgery (GTCRG) of the Spanish Society of Nuclear Medicine and Molecular Imaging (SEMNIM). Material and methods: In October 2020, the form was sent in digital format to the different nuclear medicine services in Spain. A response time of 2months with an overtime of 15 days was given. The number of ROLL/SNOLL procedures in each centre and the methodology used were obtained, including important technical details. In addition, a specific section on 125I seeds was included. The results were automatically downloaded into an Excel 2007 spreadsheet for subsequent analysis with the same program. Results: The survey was answered by 55 centres; 21 use wire-guided localisation while the remaining 34 use different radioguided surgery techniques (RGS) for the localisation of non-palpable breast lesions, with the results itemized into thirteen sections. The commonly used tracer dose is 111 MBq for the ROLL technique and 222 MBq for the SNOLL technique, with a volume of 0.2ml. The most common protocol is the two-day protocol. 26% of centres performing CRG use 125I seeds for both breast lesion and suspicious/pathological node detection, with the time between implantation and removal being about 3 days, with subsequent radiological control in most cases. Conclusion: The survey shows the relevance of radioguided surgery in the management of breast cancer patients at different stages of the disease, with disparity in the implementation of new techniques and tools, which responds to the multiple healthcare realities of Nuclear Medicine services (AU)


Assuntos
Humanos , Feminino , Neoplasias da Mama/cirurgia , Neoplasias da Mama/diagnóstico , Medicina Nuclear , Biópsia de Linfonodo Sentinela , Cirurgia Assistida por Computador , Pesquisas sobre Atenção à Saúde , Radioisótopos do Iodo , Imagem Molecular , Sociedades Médicas , Espanha
6.
Methods Mol Biol ; 2524: 457-469, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35821492

RESUMO

Angiogenesis is a prerequisite for tumor growth and invasion, and anti-angiogenesis has become a highlight in tumor treatment research. However, so far, there is no reliable solution for how to simultaneously visualize the relationship between tumor progression and angiogenesis. Bioluminescence imaging (BLI) has been broadly utilized and is a very promising non-invasive imaging technique with the advantages of low cost, high sensitivity, and robust specificity. In this chapter, we describe a dual bioluminescence imaging BLI protocol for tumor progression and angiogenesis through implanting murine breast cancer cell line 4T1 which stably expressing Renilla luciferase (RLuc) into the transgenic mice with angiogenesis-induced firefly luciferase (FLuc) expression. This modality enables us to synchronously monitor the tumor progression and angiogenesis in the same mouse, which has broad applicability in oncology studies.


Assuntos
Medições Luminescentes , Neovascularização Patológica , Animais , Luciferases de Vaga-Lume , Medições Luminescentes/métodos , Camundongos , Camundongos Transgênicos , Imagem Molecular , Neovascularização Patológica/metabolismo
7.
Methods Mol Biol ; 2525: 47-59, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35836060

RESUMO

By virtue of its high sensitivity, bioluminescence imaging (BLI) is an important tool for biosensing and bioimaging in life sciences. Compared to fluorescence imaging (FLI), BLI has a superior advantage that the background signals resulting from autofluorescence are almost zero due to the unnecessity of external excitation. In addition, BLI can permit a long-term observation of living cells because BL results in very low photocytotoxicity toward the host cells. Although BLI has such superior properties over FLI, the available wavelengths in BLI are mostly limited to the visible region. Here we present bioluminescence resonance energy transfer (BRET)-based visible and near-infrared dual-color molecular imaging using a quantum dot (QD) and luciferase-protein conjugate.


Assuntos
Pontos Quânticos , Transferência de Energia , Transferência Ressonante de Energia de Fluorescência/métodos , Luciferases/metabolismo , Medições Luminescentes/métodos , Imagem Molecular/métodos
8.
Int J Mol Sci ; 23(13)2022 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-35806074

RESUMO

Extensive angiogenesis is a characteristic feature in the synovial tissue of rheumatoid arthritis (RA) from a very early stage of the disease onward and constitutes a crucial event for the development of the proliferative synovium. This process is markedly intensified in patients with prolonged disease duration, high disease activity, disease severity, and significant inflammatory cell infiltration. Angiogenesis is therefore an interesting target for the development of new therapeutic approaches as well as disease monitoring strategies in RA. To this end, nuclear imaging modalities represent valuable non-invasive tools that can selectively target molecular markers of angiogenesis and accurately and quantitatively track molecular changes in multiple joints simultaneously. This systematic review summarizes the imaging markers used for single photon emission computed tomography (SPECT) and/or positron emission tomography (PET) approaches, targeting pathways and mediators involved in synovial neo-angiogenesis in RA.


Assuntos
Artrite Reumatoide , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/metabolismo , Biomarcadores/metabolismo , Humanos , Imagem Molecular , Neovascularização Patológica/diagnóstico por imagem , Neovascularização Patológica/metabolismo , Tomografia por Emissão de Pósitrons , Membrana Sinovial/diagnóstico por imagem , Membrana Sinovial/metabolismo
9.
Int J Mol Sci ; 23(13)2022 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-35806117

RESUMO

Imaging the interaction of individual cells with their surrounding tissue microenvironment is essential to advance in bioprinting, tissue engineering and cancer biology, to mention just three highly relevant fields in the life sciences [...].


Assuntos
Bioimpressão , Impressão Tridimensional , Bioimpressão/métodos , Microambiente Celular , Imagem Molecular , Engenharia Tecidual/métodos , Tecidos Suporte
10.
Proc Natl Acad Sci U S A ; 119(29): e2114365119, 2022 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-35858333

RESUMO

Molecular analysis on the single-cell level represents a rapidly growing field in the life sciences. While bulk analysis from a pool of cells provides a general molecular profile, it is blind to heterogeneities between individual cells. This heterogeneity, however, is an inherent property of every cell population. Its analysis is fundamental to understanding the development, function, and role of specific cells of the same genotype that display different phenotypical properties. Single-cell mass spectrometry (MS) aims to provide broad molecular information for a significantly large number of cells to help decipher cellular heterogeneity using statistical analysis. Here, we present a sensitive approach to single-cell MS based on high-resolution MALDI-2-MS imaging in combination with MALDI-compatible staining and use of optical microscopy. Our approach allowed analyzing large amounts of unperturbed cells directly from the growth chamber. Confident coregistration of both modalities enabled a reliable compilation of single-cell mass spectra and a straightforward inclusion of optical as well as mass spectrometric features in the interpretation of data. The resulting multimodal datasets permit the use of various statistical methods like machine learning-driven classification and multivariate analysis based on molecular profile and establish a direct connection of MS data with microscopy information of individual cells. Displaying data in the form of histograms for individual signal intensities helps to investigate heterogeneous expression of specific lipids within the cell culture and to identify subpopulations intuitively. Ultimately, t-MALDI-2-MSI measurements at 2-µm pixel sizes deliver a glimpse of intracellular lipid distributions and reveal molecular profiles for subcellular domains.


Assuntos
Imagem Molecular , Análise de Célula Única , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Técnicas de Cultura de Células , Metabolismo dos Lipídeos , Imagem Molecular/métodos , Análise Multivariada , Análise de Célula Única/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos
11.
Mol Imaging ; 2022: 5447290, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35903245

RESUMO

Background: Early detection and complete resection are important prognostic factors for esophageal cancer (EC). Intraoperative molecular imaging (IMI) using tumor-targeted tracers is effective in many cancer types. However, there are no EC-specific IMI tracers. We sought to test a cathepsin activity-based tracer (VGT-309) for EC resection. Methods: Murine (AKR, HNM007) and human (OE19) EC cell lines were screened for cathepsin expression by western blotting. In vitro binding affinity of VGT-309 was evaluated by fluorescence microscopy. Flank tumor models were developed by injecting EC cells into the flanks of BALB/c or athymic nude mice. Mice pretreated with a cathepsin inhibitor (JPM-OEt) were used to confirm on target binding. Animals were injected with 2 mg/kg VGT-309, underwent IMI, and were sacrificed 24 hours after injection. Results: Cathepsins B, L, S, and X were expressed by EC cell lines, and all cell lines were labeled in vitro with VGT-309. Fluorescent signal was eliminated when cells were pretreated with JPM-OEt. On biodistribution analysis, VGT-309 accumulated in the liver, kidneys, and spleen without other organ involvement. VGT-309 selectively accumulated in flank allografts and xenografts, with mean signal-to-background ratio of 5.21 (IQR: 4.18-6.73) for flank allografts and 4.34 (IQR: 3.75-5.02) for flank xenografts. Fluorescence microscopy and histopathological analysis confirmed the selective accumulation of the tracer in tumors compared to background normal tissues. Conclusions: VGT-309 is an effective tracer for IMI of esophageal cancer. There is potential for clinical translation both as an adjunct to endoscopic detection and for complete removal of disease during esophagectomy.


Assuntos
Neoplasias Esofágicas , Animais , Catepsinas/metabolismo , Linhagem Celular Tumoral , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/cirurgia , Humanos , Camundongos , Camundongos Nus , Imagem Molecular , Distribuição Tecidual
12.
Analyst ; 147(15): 3570-3577, 2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35816051

RESUMO

Lipid droplets (LDs) have emerged as a hot target for cancer therapeutics in recent years owing to findings that have shown them to be key organelles involved in maintaining cellular stability and regulating inter-organelle communication through molecular trafficking. LDs emerge from the endoplasmic reticulum (ER) as a form of cellular homeostasis control. We herein report the study of a library of asymmetric squaraines as superior fluorescence probes to track and image LDs in their native state and environment within cancer cells. The probes are highly selective towards LDs and displayed prominent bright fluorescence with just 1 µM probe concentration. They also possess bimodal LD and ER staining capability via the simple diffusion of small lipophilic molecules. The probes almost instantly stained LDs, while the ER staining rate is dependent on the probe's lipophilicity and the incubation duration. These "on-demand" organelle-selective probes are highly desirable tools for revealing the role of LDs in governing many cellular processes, especially in malignant cells.


Assuntos
Gotículas Lipídicas , Sobrevivência Celular , Ciclobutanos , Retículo Endoplasmático/metabolismo , Gotículas Lipídicas/metabolismo , Imagem Molecular , Fenóis , Coloração e Rotulagem
14.
Oncol Rep ; 48(2)2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35775375

RESUMO

The clinical introduction of molecular imaging for the management of oropharyngeal squamous cell carcinoma (OPSCC) relies on the identification of relevant cancer­specific biomarkers. The application of three membrane­bound receptors, namely urokinase­type plasminogen activator receptor (uPAR), tissue factor (TF) and EGFR have been previously explored for targeted imaging and therapeutic strategies in a broad range of solid cancers. The present study aimed to investigate the expression patterns of uPAR, EGFR and TF by immunohistochemistry (IHC) to evaluate their potential for targeted imaging and prognostic value in OPSCC. In a retrospective cohort of 93 patients with primary OPSCC, who were balanced into the 45 human papillomavirus (HPV)­positive and 48 HPV­negative groups, the IHC­determined expression profiles of uPAR, TF and EGFR in large biopsy or tumor resection specimens were analyzed. Using the follow­up data, overall survival (OS) and recurrence­free survival were measured. Specifically, associations between survival outcome, biomarker expression and clinicopathological factors were examined using Cox proportional hazards model and log­rank test following Kaplan­Meier statistics. After comparing the expression pattern of biomarkers within the tumor compartment with that in the adjacent normal tissues, uPAR and TF exhibited a highly tumor­specific expression pattern, whereas EGFR showed a homogeneous expression within the tumor compartment as well as a consistent expression in the normal mucosal epithelium and salivary gland tissues. The positive expression rate of uPAR, TF and EGFR in the tumors was 98.9, 76.3 and 98.9%, respectively. No statistically significant association between biomarker expression and survival outcome could be detected. Higher uPAR expression levels had a trend towards reduced OS according to results from univariate analysis (P=0.07; hazard ratio=2.01; 95% CI=0.92­4.37). Taken together, these results suggest that uPAR, TF and EGFR may be suitable targets for molecular imaging and therapy in OPSCC. In particular, uPAR may be an attractive target owing to their high positive expression rates in tumors and a highly tumor­specific expression pattern.


Assuntos
Neoplasias Orofaríngeas , Infecções por Papillomavirus , Carcinoma de Células Escamosas de Cabeça e Pescoço , Biomarcadores Tumorais/biossíntese , Receptores ErbB/biossíntese , Humanos , Imagem Molecular , Terapia de Alvo Molecular , Neoplasias Orofaríngeas/diagnóstico por imagem , Neoplasias Orofaríngeas/tratamento farmacológico , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/virologia , Papillomaviridae , Infecções por Papillomavirus/diagnóstico por imagem , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/patologia , Prognóstico , Receptores de Ativador de Plasminogênio Tipo Uroquinase/biossíntese , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico por imagem , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Tromboplastina/biossíntese
15.
Mol Pharm ; 19(7): 2583-2594, 2022 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-35696536

RESUMO

Daratumumab (DARA) is an anti-CD38 monoclonal antibody for the treatment of multiple myeloma (MM). The tumor CD38 expression level is one of the important factors in determining the efficacy of DARA treatment. Therefore, there is an urgent clinical need for a noninvasive tool to evaluate the CD38 levels in cancer patients before, during, and after DARA treatment. In this study, we prepared a new molecular imaging probe 99mTc-CD3813, the 99mTc-labeled nanobody CD3813, for noninvasive imaging of CD38 expression by single photon emission computed tomography (SPECT). We evaluated 99mTc-CD3813 for its CD38 affinity and specificity and its capacity to image the CD38 expression in the MM and lymphoma xenografts models. 99mTc-CD3813 SPECT/CT is able to visualize subcutaneous/orthotopic myeloma lesions in animal models and has advantages over 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography. Excess DARA has less impact on its tumor uptake (3.14 ± 0.83 vs 2.29 ± 0.91 %ID/g, n.s.), strongly suggesting that there is no competition between 99mTc-CD3813 and DARA in binding to CD38. 99mTc-CD3813 SPECT/CT revealed significant reduction in CD38 expression in the Ramos-bearing mice under DARA treatment, as evidenced by their reduced tumor uptake (3.04 ± 0.70 vs 1.07 ± 0.28 %ID/cc, P < 0.001). 99mTc-CD3813 SPECT/CT was also able to detect the increased tumor uptake (0.79 ± 0.29 vs 2.12 ± 0.12 %ID/cc, P < 0.001) due to the upregulation of CD38 levels caused by all-trans retinoic acid infection. 99mTc-CD3813 is a promising SPECT radiotracer for imaging the CD38-positive tumors and has clinical potential as a molecular imaging tool for evaluation of the CD38 expression level in patients before, during, and after DARA treatment.


Assuntos
Mieloma Múltiplo , Animais , Linhagem Celular Tumoral , Fluordesoxiglucose F18 , Humanos , Camundongos , Imagem Molecular/métodos , Sondas Moleculares , Mieloma Múltiplo/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada de Emissão de Fóton Único/métodos
17.
Cancer Imaging ; 22(1): 25, 2022 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-35659779

RESUMO

Neuroendocrine neoplasia (NEN) is an umbrella term that includes a widely heterogeneous disease group including well-differentiated neuroendocrine tumours (NETs), and aggressive neuroendocrine carcinomas (NECs). The site of origin of the NENs is linked to the intrinsic tumour biology and is predictive of the disease course. It is understood that NENs demonstrate significant biologic heterogeneity which ultimately translates to widely varying clinical presentations, disease course and prognosis. Thus, significant emphasis is laid on the pre-therapy evaluation of markers that can help predict tumour behavior and dynamically monitors the response during and after treatment. Most well-differentiated NENs express somatostatin receptors (SSTRs) which make them appropriate for peptide receptor radionuclide therapy (PRRT). However, the treatment outcomes of PRRT depend heavily on the adequacy of patient selection by molecular imaging phenotyping not only utilizing pre-treatment SSTR PET but 18F-Fluorodeoxyglucose (18F-FDG) PET to provide insights into the intra- or inter-tumoural heterogeneity of the metastatic disease. Molecular imaging phenotyping may go beyond patient selection and provide useful information during and post-treatment for monitoring of temporal heterogeneity of the disease and dynamically risk-stratify patients. In addition, advances in the understanding of genomic-phenotypic classifications of pheochromocytomas and paragangliomas led to an archetypical example in precision medicine by utilizing molecular imaging phenotyping to guide radioligand therapy. Novel non-SSTR based peptide receptors have also been explored diagnostically and therapeutically to overcome the tumour heterogeneity. In this paper, we review the current molecular imaging modalities that are being utilized for the characterization of the NENs with special emphasis on their role in patient selection for radioligand therapy.


Assuntos
Tumores Neuroendócrinos , Fluordesoxiglucose F18 , Humanos , Imagem Molecular , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/radioterapia , Prognóstico , Receptores de Somatostatina
18.
J Nanobiotechnology ; 20(1): 267, 2022 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-35689262

RESUMO

Triple-negative breast cancer (TNBC) is a highly heterogeneous breast cancer subtype with poor prognosis. Although anatomical imaging figures prominently for breast lesion screening, TNBC is often misdiagnosed, thus hindering early medical care. Ultrasound (US) molecular imaging using nanobubbles (NBs) capable of targeting tumor cells holds great promise for improved diagnosis and therapy. However, the lack of conventional biomarkers in TNBC impairs the development of current targeted agents. Here, we exploited the homotypic recognition of cancer cells to synthesize the first NBs based on TNBC cancer cell membrane (i.e., NBCCM) as a targeted diagnostic agent. We developed a microfluidic technology to synthesize NBCCM based on the self-assembly property of cell membranes in aqueous solutions. In vitro, optimal NBCCM had a hydrodynamic diameter of 683 ± 162 nm, showed long-lasting US contrast enhancements and homotypic affinity. In vivo, we demonstrated that NBCCM showed increased extravasation and retention in a TNBC mouse model compared to non-targeted NBs by US molecular imaging. Peak intensities and areas under the curves from time-intensity plots showed a significantly enhanced signal from NBCCM compared to non-targeted NBs (2.1-fold, P = 0.004, and, 3.6-fold, P = 0.0009, respectively). Immunofluorescence analysis further validated the presence of NBCCM in the tumor microenvironment. Circumventing the challenge for universal cancer biomarker identification, our approach could enable TNBC targeting regardless of tumor tissue heterogeneity, thus improving diagnosis and potentially gene/drug targeted delivery. Ultimately, our approach could be used to image many cancer types using biomimetic NBs prepared from their respective cancer cell membranes.


Assuntos
Neoplasias de Mama Triplo Negativas , Animais , Biomimética , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Nus , Imagem Molecular/métodos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Microambiente Tumoral
19.
Cancer Imaging ; 22(1): 31, 2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35729608

RESUMO

The goals of precision oncology are to provide targeted drug therapy based on each individual's specific tumor biology, and to enable the prediction and early assessment of treatment response to allow treatment modification when necessary. Thus, precision oncology aims to maximize treatment success while minimizing the side effects of inadequate or suboptimal therapies. Molecular imaging, through noninvasive assessment of clinically relevant tumor biomarkers across the entire disease burden, has the potential to revolutionize clinical oncology, including breast oncology. In this article, we review breast cancer positron emission tomography (PET) imaging biomarkers for providing early response assessment and predicting treatment outcomes. For 2-18fluoro-2-deoxy-D-glucose (FDG), a marker of cellular glucose metabolism that is well established for staging multiple types of malignancies including breast cancer, we highlight novel applications for early response assessment. We then review current and future applications of novel PET biomarkers for imaging the steroid receptors, including the estrogen and progesterone receptors, the HER2 receptor, cellular proliferation, and amino acid metabolism.


Assuntos
Neoplasias da Mama , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Feminino , Fluordesoxiglucose F18/uso terapêutico , Humanos , Imagem Molecular/métodos , Tomografia por Emissão de Pósitrons/métodos , Medicina de Precisão , Compostos Radiofarmacêuticos/uso terapêutico
20.
Theranostics ; 12(9): 4446-4458, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35673571

RESUMO

Background: Radiolabeled agents that are substrates for the norepinephrine transporter (NET) can be used to quantify cardiac sympathetic nervous conditions and have been demonstrated to identify high-risk congestive heart failure (HF) patients prone to arrhythmic events. We aimed to fully characterize the kinetic profile of the novel 18F-labeled NET probe AF78 for PET imaging of the cardiac sympathetic nervous system (SNS) among various species. Methods: 18F-AF78 was compared to norepinephrine (NE) and established SNS radiotracers by employing in vitro cell assays, followed by an in vivo PET imaging approach with healthy rats, rabbits and nonhuman primates (NHPs). Additionally, chase protocols were performed in NHPs with NET inhibitor desipramine (DMI) and the NE releasing stimulator tyramine (TYR) to investigate retention kinetics in cardiac SNS. Results: Relative to other SNS radiotracers, 18F-AF78 showed higher transport affinity via NET in a cell-based competitive uptake assay (IC50 0.42 ± 0.14 µM), almost identical to that of NE (IC50, 0.50 ± 0.16 µM, n.s.). In rabbits and NHPs, initial cardiac uptake was significantly reduced by NET inhibition. Furthermore, cardiac tracer retention was not affected by a DMI chase protocol but was markedly reduced by intermittent TYR chase, thereby suggesting that 18F-AF78 is stored and can be released via the synaptic vesicular turnover process. Computational modeling hypothesized the formation of a T-shaped π-π stacking at the binding site, suggesting a rationale for the high affinity of 18F-AF78. Conclusion: 18F-AF78 demonstrated high in vitro NET affinity and advantageous in vivo radiotracer kinetics across various species, indicating that 18F-AF78 is an SNS imaging agent with strong potential to guide specific interventions in cardiovascular medicine.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Norepinefrina , Compostos Radiofarmacêuticos , Animais , Biomarcadores , Radioisótopos de Flúor , Humanos , Imagem Molecular , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Coelhos , Ratos
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